title: Reduced cytochrome C is an essential regulator of sustained insulin secretion by pancreatic islets.
abstract: Influx of calcium is an essential but insufficient signal in sustained nutrient-stimulated insulin secretion, and increased metabolic rate of the beta cell is also required. The aim of the study was to test the hypothesis that the reduced state of cytochrome c is a metabolic co-factor necessary for insulin secretion, over and above its participation in the ATP-generating function of electron transport/oxidative phosphorylation. We found that nutrient stimulation of insulin secretion by isolated rat islets was strongly correlated with reduced cytochrome c, and agents that acutely and specifically reduced cytochrome c led to increased insulin secretion, even in the face of decreased oxygen consumption and calcium influx. In contrast, neither sites 1 nor 4 of the electron transport chain were both necessary and essential for the stimulation of insulin secretion to occur. Importantly, stimulation of islets with glucose, α-ketoisocaproate, or glyceraldehyde resulted in the appearance of cytochrome c in the cytosol, suggesting a pathway for the regulation of exocytotic machinery by reduction of cytochrome c. The data suggest that the metabolic factor essential for sustained calcium-stimulated insulin secretion to occur is linked to reduction and translocation of cytochrome c.
authors.affiliation: Department of Medicine, Diabetes and Obesity Center, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Seung-Ryoung
authors.initials: SR
authors.lastname: Jung
authors.forename: Iok Teng Denise
authors.initials: IT
authors.lastname: Kuok
authors.forename: Drew
authors.initials: D
authors.lastname: Couron
authors.forename: Norma
authors.initials: N
authors.lastname: Rizzo
authors.forename: Daciana H
authors.initials: DH
authors.lastname: Margineantu
authors.forename: David M
authors.initials: DM
authors.lastname: Hockenbery
authors.forename: Francis
authors.initials: F
authors.lastname: Kim
authors.forename: Ian R
authors.initials: IR
authors.lastname: Sweet
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism*; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D045222:Electron Transport Chain Complex Proteins; D007328:Insulin; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D002118:Calcium